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JP-7857235-B2 - Methods for treating or preventing chronic kidney disease

JP7857235B2JP 7857235 B2JP7857235 B2JP 7857235B2JP-7857235-B2

Inventors

  • イェー，リテイン
  • イェン，シュンチー
  • イェン，ロンチ
  • シェン，ザンツォン

Assignees

  • アースローシ セラピューティクス，インク．

Dates

Publication Date
20260512
Application Date
20210609
Priority Date
20200610

Claims (10)

  1. A pharmaceutical composition for use in the treatment or prevention of chronic kidney disease , The present invention comprises a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7- d4 )methanone, and at least one inactive component selected from pharmaceutically acceptable carriers, diluents , and excipients. The effective therapeutic dose is approximately 10 mg to approximately 200 mg. The aforementioned therapeutically effective dose is administered orally. The aforementioned therapeutically effective dose is administered once a day. Pharmaceutical composition.
  2. The pharmaceutical composition according to claim 1, wherein the therapeutically effective dose is approximately 10 mg to approximately 100 mg.
  3. The pharmaceutical composition according to claim 2, wherein the therapeutically effective dose is approximately 75 mg.
  4. The pharmaceutical composition according to claim 2, wherein the therapeutically effective dose is approximately 50 mg.
  5. A pharmaceutical composition according to any one of claims 1 to 4 , further comprising a xanthine oxidase inhibitor.
  6. The pharmaceutical composition according to claim 5 , wherein the xanthine oxidase inhibitor is allopurinol, oxypurinol, febuxostat, topiroxostat, or inositol.
  7. The pharmaceutical composition according to claim 5, wherein the xanthine oxidase inhibitor is allopurinol.
  8. The pharmaceutical composition according to claim 5, wherein the xanthine oxidase inhibitor is febuxostat.
  9. A pharmaceutical composition according to any one of claims 1 to 4 , further comprising an SGLT2 inhibitor.
  10. The pharmaceutical composition according to claim 9 , wherein the SGLT2 inhibitor is canagliflozin, dapagliflozin, or empagliflozin .

Description

Cross-reference This application claims the benefits of U.S. Provisional Application No. 63/037,469 filed on 10 June 2020 and U.S. Provisional Application No. 63/195,411 filed on 1 June 2021, both of which are incorporated herein by reference in their entirety. Chronic kidney disease refers to the progressive loss of kidney function. The kidneys filter waste products and excess fluids from the blood, which are then excreted in the urine. When chronic kidney disease progresses, dangerous levels of fluid, electrolytes, and waste products can accumulate in the body. Chronic kidney disease can progress to end-stage renal failure, which is fatal without dialysis or a kidney transplant. The mean plasma concentration profiles of compound 1 following a single oral administration of compound 1 (15 mg, 50 mg, 100 mg, and 150 mg) in a fasted state are illustrated.This illustrates the mean plasma concentration profile of compound 1 following a single oral administration of 50 mg of compound 1 in a fasted versus fed state.This example illustrates the dose-proportionality of compound 1 AUC following a single oral administration of compound 1 (15 mg, 50 mg, 100 mg, and 150 mg) in a fasted state.This example illustrates the dose-proportionality of compound 1 C max following a single oral administration of compound 1 (15 mg, 50 mg, 100 mg, and 150 mg) in a fasted state.The mean serum uric acid levels (mg/dL) following a single oral administration of compound 1 at various doses under fasting conditions are illustrated.The figures illustrate the mean time-adjusted (Day 1) percentage change in serum uric acid concentration from baseline following a single oral administration of compound 1 at various doses under fasting conditions.The diagram illustrates the mean time-adjusted (Day 1) percentage change in serum uric acid concentration from baseline following a single oral administration of 50 mg of compound 1 in a fasted versus fed state.The mean plasma concentration profiles of compound 1 following 10 days of once-daily oral administration of compound 1 at various doses under fasting conditions are illustrated.The mean serum uric acid levels (mg/dL) following 10 days of once-daily oral administration of compound 1 at various doses under fasting conditions are illustrated.The diagram illustrates the mean time-adjusted (day 1) percentage change in serum uric acid concentration from baseline following 10 days of once-daily oral administration of compound 1 at various doses under fasting conditions. Benzbromarone is an effective uric acid excretort that lowers serum uric acid (sUA). Treatment with benzbromarone has been found to reduce sUA even after a single dose, and to continue to reduce it further after multiple doses, and chronic treatment can bring sUA to a target level of <6 mg/dL. However, in certain patients, benzbromarone is associated with hepatotoxicity. A high percentage of these patients developed acute liver failure leading to death or emergency liver transplantation. As a result, benzbromarone was not approved for use in the United States. In addition, the hepatotoxicity of benzbromarone led to its withdrawal in Europe in 2003. Benzbromarone is converted to a reactive metabolite by CYP2C9. Benzbromarone is metabolized by CYP2C9 via 6-OH benzbromarone to 5,6-dihydroxybenzbromarone, and subsequently to a reactive ortho-quinone intermediate by oxidation of 5,6-dihydroxybenzbromarone. The mechanism of benzbromarone hepatotoxicity is thought to be a result of its hepatic metabolism by CYP2C9, as well as the possible effects of its further metabolites on 6-OH benzbromarone and mitochondrial function (Iwamura et al., Drug Metabolism and Disposition, 2011, 39, 838-846; Uchida et al., Drug Metabolism. Pharmacokinet., 2010, 25, 605-610). (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7- d4 )methanone (Compound 1), a 4,5,6,7-tetradutero analog of benzbromarone, is described herein. Compound 1 showed better in vitro URAT1 efficacy than benzbromarone. Compound 1 also demonstrated an improved metabolic profile compared to benzbromarone. Compound 1 is more stable than benzbromarone in human microsomes. The compound's CYP2C9 metabolic pathway is significantly reduced, and no 6-OH benzbromarone or 5,6-di-OH benzbromarone metabolites are formed. Therefore, Compound 1 represents a promising therapeutic agent for the treatment or prevention of chronic kidney disease with an improved hepatotoxicity profile. In addition, Compound 1 is a promising therapeutic agent for the treatment or prevention of heart failure. Compound 1 In one embodiment, the compound is (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7- d4 )methanone. Compound 1 or (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7- d4 )methanone has the following structure: This refers to compounds that possess [a certain characteristic]. In some embodiments, compound 1 includes a solvent-added form (solvate). The s